Down-regulation of the Wnt/β-catenin signaling pathway by Cacnb4
Rima, Mohamad
Daghsni, Marwa
Lopez, Anaïs
Fajloun, Ziad
Lefrancois, Lydie
Dunach, Mireia (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Merle, Philippe
Brusés, Juan L.
De Waard, Michel
Ronjat, Michel

Data:	2017
Resum:	The cytoplasmic β-subunit of the voltage-gated calcium channels has been shown be involved in the regulation of gene transcription. This subunit interacts with the transcription factor TCF4 and inhibits the Wnt/β-catenin signaling pathway. These results may also explain the inhibitory effect of the β-subunit on cell proliferation. The β isoform of the β-subunits of voltage-gated calcium channel regulates cell proliferation and cell cycle progression. Herein we show that coexpression of the β-subunit with actors of the canonical Wnt/β-catenin signaling pathway in a hepatoma cell line inhibits Wnt-responsive gene transcription and decreases cell division, in agreement with the role of the Wnt pathway in cell proliferation. β-subunit-mediated inhibition of Wnt signaling is observed in the presence of LiCl, an inhibitor of glycogen synthase kinase (GSK3) that promotes β-catenin translocation to the nucleus. Expression of β-subunit mutants that lost the ability to translocate to the nucleus has no effect on Wnt signaling, suggesting that β-subunit inhibition of Wnt signaling occurs downstream from GSK3 and requires targeting of β-subunit to the nucleus. β-subunit coimmunoprecipitates with the TCF4 transcription factor and overexpression of TCF4 reverses the effect of β-subunit on the Wnt pathway. We thus propose that the interaction of nuclear β-subunit with TCF4 prevents β-catenin binding to TCF4 and leads to the inhibition of the Wnt-responsive gene transcription. Thereby, our results show that β-subunit is a TCF4 repressor and therefore appears as an interesting candidate for the regulation of this pathway in neurons where β-subunit is specifically expressed.
Nota:	Altres ajuts: Mohamad Rima is supported by a doctoral fellowship from the Azm& Saade Association. The Laboratory of Excellence "Ion Channels,Science and Therapeutics" consortium is supported by Agence Nationale de la Recherche Grant No. ANR-11-LABX-0015.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra, i la creació d'obres derivades, sempre que no sigui amb finalitats comercials i que es distribueixin sota la mateixa llicència que regula l'obra original. Cal que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Molecular biology of the cell, Vol. 28 (december 2017) , p. 3699-3708, ISSN 1939-4586

DOI: 10.1091/mbc.E17-01-0076
PMID: 29021340

10 p, 1.9 MB

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